In the United States two percent of deaths from cancer result from melanomas. During the last decade the frequency of deaths from melanomas has doubled. Unless initial surgical excision of a melanoma is complete and occurs before any metastases, the outcome is inevitably fatal. There is no treatment for the disease. Our goal is the solution of the problem of melanomas. We want to find out how normal melanocytes are transformed into melanomas, how melanomas can be detected soon after they occur, how the growth of melanomas can be controlled and how the formation of melanomas can be prevented. We have combined expertise in chemistry, biochemistry, cell biology and genetics in a cooperative effort to elucidate aspects of the growth of melanoma cells and the biosynthesis of melanin. The main thrust of our experiments involves the use of mouse melanoma cells in culture. We are using these cells as a model for all aspects of pigment biosynthesis and the growth of melanomas. Where possible and relevant we are studying melanomas in mice of a variety of genetic background. The specific aims of this proposal are: 1. Studies on MSH-induced pigmentation in melanoma cells. 2. Studies on relationships between proliferation and pigmentation. 3. Studies on diagnosis and chemotherapy of melanomas. Enormous progress has been made by us and others in the study of the basic and applied biology of melanomas. We believe that four distinct approaches are required. The first concerns receptors for MSH; the second requires the development of techniques to grow normal melanocytes in culture, and the study of the regulation of proliferation of melanoma cells; the third centers on the cytotoxicity of melanin precursors; and MSH-toxin conjugates and the fourth involves the immunology of melanocytes. This proposal covers the first three topics.